Brown Adipose Research Articles

Succinic Acid Improves the Metabolism of High-Fat Diet-Induced Mice and Promotes White Adipose Browning

Succinic acid plays a crucial role as an essential intermediate in the mitochondrial tricarboxylic acid cycle in mitochondria. In recent years, growing evidence has supported the the important role of succinic acid in fat metabolism. Therefore, we aimed to investigate the effects of succinic acid on adipose tissue metabolism and insulin sensitivity in high-fat diet (HFD)-induced obese mice and try to explore its potential mechanism. We found that the addition of succinic acid (40 mM) to drinking water inhibited the hypertrophy of inguinal white adipose tissue (iWAT) in HFD-induced mice. Furthermore, succinic acid supplementation enhanced insulin sensitivity and improved their glucose tolerance in obese mice. Interestingly, succinic acid supplementation improved lipid metabolism in HFD-fed mice, as shown by decreased serum levels of TG, TC, LDL-C, and increased HDL-C. In addition, succinic acid supplementation increased the expression of browning markers and mitochondria-related genes in iWAT. Further studies showed that the addition of succinic acid to drinking water promotes the browning of iWAT by activating the PI3K-AKT/MAPK signaling pathway. These results suggest that succinic acid has the potential to be used as an effective component for dietary intervention and may, therefore, play an important role in ameliorating and preventing obesity and associated metabolic diseases caused by HFD.

Regulatory effects of yam (Dioscorea opposita Thunb.) glycoprotein on energy metabolism in C2C12 and 3T3-L1 cells and on crosstalk between these two cells

Ethnopharmacological relevanceControlling energy and regulating metabolism have been key strategies in the treatment of metabolic disorders such as obesity. Yam glycoprotein (Y-Gly) is a polysaccharide-protein complex extracted from Chinese yam that has beneficial effects on glucose and lipid metabolism. This study aimed to investigate the role of Y-Gly in regulating energy metabolism in C2C12 and 3T3-L1 cells. Materials and methodsY-Gly was subjected to extraction and chemo-profiling. Staining methods, assay kits, Western Blot and transcriptomics were mainly used to determine the role of Y-Gly. Additionally, the study sought to examine the impact of Y-Gly on white adipose browning in 3T3-L1 cells, employing a cell co-culture technique. ResultsY-Gly promoted myotube differentiation in C2C12 myoblasts, increased cellular glucose consumption, promoted ATP synthesis and mitochondrial biogenesis, and played an active role in energy expenditure and glycolipid metabolism related pathways such as AMPK and MAPK. The introduction of Y-Gly inhibited lipid accumulation after lipogenesis in 3T3-L1 cells, facilitated induction of white adipose browning related proteins such as PPARγ and UCP1 expression, and the effect was more significant after cell co-culture. ConclusionsY-Gly regulates glucose and lipid metabolism by activating the key proteins in the aforementioned pathways, and plays a role in energy metabolism regulation through crosstalk between muscle and adipose tissues. This suggests a possible role of Y-Gly in metabolism-related diseases.

Dietary vegetable Sarcochlamys pulcherrima Gaud. And its bioactive compound myricitrin promotes white adipose browning in obese models via AMPK/SIRT1/UCP1 upregulation

Obesity, a worldwide epidemic, is a metabolic disturbance marked by acute adipose inflammation in the body due to accumulation of surplus nutrients. The aim of the study is to inverse the pathological development of obesity through conversion of WAT to brown AT by employing the traditionally acclaimed fat reducing efficacy of Sarcochlamys pulcherrima Gaud. (SP), a leafy dietary vegetable, and its isolated bioactive compound Myricitrin (MR). The study was carried out using 3T3-L1 adipocytes and HF diet C57BL/6 mice treated with SPEF (SP enriched fraction) and MR. Accumulation of triglycerides, lipids and ROS were checked along with mitochondrial biogenesis. Immunoblotting for AMPK dependent mitochondrial biogenesis, browning markers, lipogenic and inflammatory proteins were checked aided by in silico analysis. Histopathological analysis of the adipose tissue was supported with immunoblotting techniques. Treatment with MR significantly reduced the triglyceride, lipid and ROS levels with elevated mitochondrial biogenesis. MR also upregulates AMPK/SIRT1 dependent browning markers: UCP1 and PRDM16 and reduces pro-inflammatory cytokines with reduced lipogenesis. Administration of SPEF 150 and 300 mg/kg b.w for 6 weeks on HF diet mice showed significant reduction in body weight, triglyceride and cholesterol levels. Histology of adipose tissue showed brown AT depots in the treated group. In silico analysis showed the activation of SIRT1 substrate with MR leading to changes in adipose tissue morphology. The overall WAT browning efficacy of S. pulcherrima and its isolated bioactive compound MR was demonstrated in the present study. Further scientific substantiations can be carried out for the development of nature-based anti-obesogenic drugs.

Brown adipose tissue‐derived exosomes improve polycystic ovary syndrome in mice via STAT3/GPX4 signaling pathway

AbstractPolycystic ovary syndrome (PCOS) is associated with impaired adipose tissue physiology. Elevated brown adipose tissue (BAT) mass or activity has shown potential in the treatment of PCOS. In this study, we aimed to investigate whether BAT‐derived exosomes (BAT‐Exos), as potential biomarkers of BAT activity, exert similar benefits as BAT in the treatment of PCOS. PCOS was induced in female C57BL/6J mice orally administered 1 mg/kg of letrozole for 21 days. Subsequently, the animals underwent transplantation with BAT or administered BAT‐Exos (200 μg) isolated from young healthy mice via the tail vein; healthy female mice were used as controls. The results indicate that BAT‐Exos treatment significantly reduced body weight and improved insulin resistance in PCOS mice. In addition, BAT‐Exos improved ovulation function by reversing the acyclicity of the estrous cycle, decreasing circulating luteinizing hormone and testosterone, recovering ovarian performance, and improving oocyte quality, leading to a higher pregnancy rate and litter size. Furthermore, western blotting revealed reduced expression of signal transducer and activator of transcription 3 (STAT3) and increased expression of glutathione peroxidase 4 (GPX4) in the ovaries of mice in the BAT‐Exos group. To further explore the role of the STAT3/GPX4 signaling pathway in PCOS mice, we treated the mice with an intraperitoneal injection of 5 mg/kg stattic, a STAT3 inhibitor. Consistent with BAT‐Exos treatment, the administration of stattic rescued letrozole‐induced PCOS phenotypes. These findings suggest that BAT‐Exos treatment might be a potential therapeutic strategy for PCOS and that the STAT3/GPX4 signaling pathway is a critical therapeutic target for PCOS.

Glutathione peroxidase 3 is essential for countering senescence in adipose remodelling by maintaining mitochondrial homeostasis

Adipose tissue senescence is a precursor to organismal aging and understanding adipose remodelling contributes to discovering novel anti-aging targets. Glutathione peroxidase 3 (GPx3), a critical endogenous antioxidant enzyme, is diminished in the subcutaneous adipose tissue (sWAT) with white adipose expansion. Based on the active role of the antioxidant system in counteracting aging, we investigated the involvement of GPx3 in adipose senescence. We determined that knockdown of GPx3 in adipose tissue by adeno-associated viruses impaired mitochondrial function in mice, increased susceptibility to obesity, and exacerbated adipose tissue senescence. Impairment of GPx3 may cause mitochondrial dysfunction through inner mitochondrial membrane disruption. Adipose reshaping management (cold stimulation and intermittent diet) counteracted the aging of tissues, with an increase in GPx3 expression. Overall metabolic improvement induced by cold stimulation was partially attenuated when GPx3 was depleted. GPx3 may be involved in adipose browning by interacting with UCP1, and GPx3 may be a limiting factor for intracellular reactive oxygen species (ROS) accumulation during stem cell browning. Collectively, these findings emphasise the importance of restoring the imbalanced redox state in adipose tissue to counteract aging and that GPx3 may be a potential target for maintaining mitochondrial homeostasis and longevity.

Intermittent Fasting-Induced Orm2 Promotes Adipose Browning via the GP130/IL23R-p38 Cascade.

Intermittent fasting (IF) plays a critical role in mitigating obesity, yet the precise biological mechanisms require further elucidation. Here Orosomucoid 2 (Orm2)is identified as an IF-induced hepatokine that stimulates adipose browning. IF induced Orm2 expression and secretion from the liver through peroxisome proliferator-activated receptor alpha (PPARα). In adipose tissue, Orm2 bound to glycoprotein 130/interleukin 23 receptor (GP130/IL23R)and promoted adipose browning through the activation of p38 mitogen-activated protein kinases (p38-MAPK). In obese mice, Orm2 led to a significant induction of adipose tissue browning and subsequent weight loss, an effect that is not replicated by a mutant variant of Orm2 deficient in GP130/IL23R binding capability. Crucially, genetic association studies in humans identified an obesity-associated Orm2 variant (D178E), which shows decreased GP130/IL23R binding and impaired browning capacity in mice. Overall, the research identifies Orm2 as a promising therapeutic target for obesity, mediating adipose browning through the GP130/IL23R-p38 signalling pathway.

Hormonal orchestra: mastering mitochondria's role in health and disease.

Mitochondria is a subcellular organelle involved in the pathogenesis of cellular stress, immune responses, differentiation, metabolic disorders, aging, and death by regulating process of fission, fusion, mitophagy, and transport. However, an increased interest in mitochondria as powerhouse for ATP production, the mechanisms of mitochondria-mediated cellular dysfunction in response to hormonal interaction remains unknown. Mitochondrial matrix contains chaperones and proteases that regulate intrinsic apoptosis pathway through pro-apoptotic Bcl-2 family's proteins Bax/Bak, and Cyt C release, and induces caspase-dependent and independent cells death. Energy and growth regulators such as thyroid hormones have profound effect on mitochondrial inner membrane protein and lipid compositions, ATP production by regulating oxidative phosphorylation system. Mitochondria contain cholesterol side-chain cleavage enzyme, P450scc, ferredoxin, and ferredoxin reductase providing an essential site for steroid hormones biosynthesis. In line with this, neurohormones such as oxytocin, vasopressin, and melatonin are correlated with mitochondrial integrity, displaying therapeutic implications for inflammatory and immune responses. Melatonin's also displayed protective role against oxidative stress and mitochondrial synthesis of ROS, suggesting a defense mechanism against aging-related diseases. An imbalance in mitochondrial bioenergetics can cause neurodegenerative disorders, cardiovascular diseases, and cancers. Hormone-induced PGC-1α stimulates mitochondrial biogenesis via activation of NRF1 and NRF2, which in turn triggers mtTFA in brown adipose and cardiac myocytes. Mitochondria can be transferred through cells merging, exosome-mediated transfer, and tunneling through nanotubes. By delineating the underlying molecular mechanism of hormonal mitochondrial interaction, this study reviews the dynamics mechanisms of mitochondria and its effects on cellular level, health, diseases, and therapeutic strategies targeting mitochondrial diseases.

Ling-gui-zhu-gan promotes adipocytes browning via targeting the miR-27b/PRDM16 pathway in 3T3-L1 cells.

Introduction: Obesity, a global epidemic, is caused by an imbalance between energy intake and expenditure. The induction of white adipose browning to increase heat production has emerged as a potential effective strategy to address obesity. Ling-gui-zhu-gan (LGZG), a traditional Chinese medicine formula, has been proved to achieve promising results to combat obesity and related metabolic diseases, yet the mechanisms remain largely unexplored. This study aimed to elucidate the anti-obesity properties and the mechanisms of LGZG by investigating its browning effect on 3T3-L1 adipocytes. Methods: LGZG-containing serum obtained by oral administration of LGZG to animals was added to 3T3-L1 adipocytes to simulate in vivo conditions. Results: The results showed that 49 compounds were identified in LGZG-containing serum by UHPLC-Q-Orbitrap HRMS, including compounds such as atractylenolides and polyporenic acid C, etc. LGZG-containing serum alleviated the lipid accumulation and decreased both intracellular and extracellular triglyceride contents in a dose-dependent manner. This reduction is accompanied by enhanced mitochondrial respiratory and heat production function. Mechanistically, LGZG-containing serum led to a decrease in miR-27b expression and an increase in the mRNA and protein levels of browning-related markers, including UCP1, PRDM16, PGC-1α, PPARγ, CTBP1, and CTBP2. Further investigation using miR-27b mimic transfection confirmed that miR-27b/PRDM16 pathway might be a potential mechanism by which LGZG-containing serum promotes browning of 3T3-L1 adipocytes. Discussion: These results underscore the therapeutic potential of LGZG in addressing obesity and its associated metabolic disorders through the promotion of adipose browning.

Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.

Dietary interventions such as caloric restriction (CR) 1 and methionine restriction 2 that prolong lifespan induce the 'browning' of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health 3,4 . However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans 5 reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH) 6 , the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

Brown Algae Ecklonia cava Extract Modulates Adipogenesis and Browning in 3T3-L1 Preadipocytes through HO-1/Nrf2 Signaling.

This study explores the anti-obesity effects of the ethyl acetate extract of Ecklonia cava (EC-ETAC) on 3T3-L1 preadipocytes, focusing on its impact on adipogenesis, lipolysis, and adipose browning via the HO-1/Nrf2 pathway. Western blot analysis revealed that EC-ETAC significantly inhibited adipogenic transcription factors (PPARγ, C/EBPα, SREBP-1) and lipogenesis-related proteins (FAS, LPL). Concurrently, EC-ETAC enhanced lipolytic markers (p-AMPK, p-HSL) and adipose browning-related proteins (UCP-1, PGC-1α), indicating its role in promoting lipolysis and adipose browning. The inhibition of HO-1 by zinc protoporphyrin (ZnPP) significantly reversed these effects, underscoring the critical role of HO-1 in mediating the anti-obesity properties of EC-ETAC. Additionally, fluorescence measurements and Oil Red O staining confirmed the reduction of lipid accumulation and oxidative stress upon EC-ETAC treatment. These findings suggest that EC-ETAC exerts its anti-obesity effects by modulating the HO-1/Nrf2 pathway, which is crucial for regulating adipogenesis, lipolysis, and adipose browning. This study highlights the potential of EC-ETAC as a natural therapeutic agent for obesity management and supports further research into its clinical applications. By targeting the HO-1/Nrf2 pathway, EC-ETAC could offer a novel approach to enhancing energy expenditure and reducing fat mass, thereby improving metabolic health.

SGLT2 inhibitor canagliflozin reduces visceral adipose tissue in db/db mice by modulating AMPK/KLF4 signaling and regulating mitochondrial dynamics to induce browning

Obesity is characterized by excessive accumulation of adipose tissue (mainly visceral). The morphology and function of mitochondria are crucial for regulating adipose browning and weight loss. Research suggests that the SGLT2 inhibitor canagliflozin may induce weight loss through an unknown mechanism, particularly targeting visceral adipose tissue. While Krueppel-Like Factor 4 (KLF4) is known to be essential for energy metabolism and mitochondrial function, its specific impact on visceral adipose tissue remains unclear. We administered canagliflozin to db/db mice for 8 weeks, or exposed adipocytes to canagliflozin for 24 h. The expression levels of browning markers, mitochondrial dynamics, and KLF4 were assessed. Then we validated the function of KLF4 through overexpression in vivo and in vitro. Adenosine monophosphate-activated protein kinase (AMPK) agonists, inhibitors, and KLF4 si-RNA were employed to elucidate the relationship between AMPK and KLF4. The findings demonstrated that canagliflozin significantly decreased body weight in db/db mice and augmented cold-induced thermogenesis. Additionally, canagliflozin increased the expression of mitochondrial fusion-related factors while reducing the levels of fission markers in epididymal white adipose tissue. These consistent findings were mirrored in canagliflozin-treated adipocytes. Similarly, overexpression of KLF4 in both adipocytes and db/db mice yielded comparable results. In all, canagliflozin mitigates obesity in db/db mice by promoting the brown visceral adipocyte phenotype through enhanced mitochondrial fusion via AMPK/KLF4 signaling.

Insulin and leptin oscillations license food-entrained browning and metabolic flexibility

Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.

Alternative isoform expression of key thermogenic genes in human beige adipocytes.

The beneficial effect of thermogenic adipocytes in maintaining body weight and protecting against metabolic disorders has raised interest in understanding the regulatory mechanisms defining white and beige adipocyte identity. Although alternative splicing has been shown to propagate adipose browning signals in mice, this has yet to be thoroughly investigated in human adipocytes. We performed parallel white and beige adipogenic differentiation using primary adipose stem cells from 6 unrelated healthy subjects and assessed differential gene and isoform expression in mature adipocytes by RNA sequencing. We find 777 exon junctions with robust differential usage between white and beige adipocytes in all 6 subjects, mapping to 562 genes. Importantly, only 10% of these differentially spliced genes are also differentially expressed, indicating that alternative splicing constitutes an additional layer of gene expression regulation during beige adipocyte differentiation. Functional classification of alternative isoforms points to a gain of function for key thermogenic transcription factors such as PPARG and CITED1, and enzymes such as PEMT, or LPIN1. We find that a large majority of the splice variants arise from differential TSS usage, with beige-specific TSSs being enriched for PPARγ and MED1 binding compared to white-specific TSSs. Finally, we validate beige specific isoform expression at the protein level for two thermogenic regulators, PPARγ and PEMT. These results suggest that differential isoform expression through alternative TSS usage is an important regulatory mechanism for human adipocyte thermogenic specification.

Development of Recombinant High-Density Lipoprotein Platform with Innate Adipose Tissue-Targeting Abilities for Regional Fat Reduction.

As an escalating public health issue, obesity and overweight conditions are predispositions to various diseases and are exacerbated by concurrent chronic inflammation. Nonetheless, extant antiobesity pharmaceuticals (quercetin, capsaicin, catecholamine, etc.) manifest constrained efficacy alongside systemic toxic effects. Effective therapeutic approaches that selectively target adipose tissue, thereby enhancing local energy expenditure, surmounting the limitations of prevailing antiobesity modalities are highly expected. In this context, we developed a temperature-sensitive hydrogel loaded with recombinant high-density lipoprotein (rHDL) to achieve targeted delivery of resveratrol, an adipose browning activator, to adipose tissue. rHDL exhibits self-regulation on fat cell metabolism and demonstrates natural targeting toward scavenger receptor class B type I (SR-BI), which is highly expressed by fat cells, thereby achieving a synergistic effect for the treatment of obesity. Additionally, the dispersion of rHDL@Res in temperature-sensitive hydrogels, coupled with the regulation of their degradation and drug release rate, facilitated sustainable drug release at local adipose tissues over an extended period. Following 24 days' treatment regimen, obese mice exhibited improved metabolic status, resulting in a reduction of 68.2% of their inguinal white adipose tissue (ingWAT). Specifically, rHDL@Res/gel facilitated the conversion of fatty acids to phospholipids (PA, PC), expediting fat mobilization, mitigating triglyceride accumulation, and therefore facilitating adipose tissue reduction. Furthermore, rHDL@Res/gel demonstrated efficacy in attenuating obesity-induced inflammation and fostering angiogenesis in ingWAT. Collectively, this engineered local fat reduction platform demonstrated heightened effectiveness and safety through simultaneously targeting adipocytes, promoting WAT browning, regulating lipid metabolism, and controlling inflammation, showing promise for adipose-targeted therapy.

The mitochondrial multi-omic response to exercise training across rat tissues

Mitochondria have diverse functions critical to whole-body metabolic homeostasis. Endurance training alters mitochondrial activity, but systematic characterization of these adaptations is lacking. Here, the Molecular Transducers of Physical Activity Consortium mapped the temporal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats trained for 1, 2, 4, or 8weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart, and skeletal muscle. The colon showed non-linear response dynamics, whereas mitochondrial pathways were downregulated in brown adipose and adrenal tissues. Protein acetylation increased in the liver, with a shift in lipid metabolism, whereas oxidative proteins increased in striated muscles. Exercise-upregulated networks were downregulated in human diabetes andcirrhosis. Knockdown of the central network protein 17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) elevated oxygen consumption, indicative of metabolic stress. We provide a multi-omic, multi-tissue, temporal atlas of the mitochondrial response to exercise training and identify candidates linked to mitochondrial dysfunction.

Spexin ameliorated obesity-related metabolic disorders through promoting white adipose browning mediated by JAK2-STAT3 pathway

BackgroundSpexin, a 14 amino acid peptide, has been reported to regulate obesity and its associated complications. However, little is known about the underlying molecular mechanism. Therefore, this study aimed to investigate the effects of spexin on obesity and explore the detailed molecular mechanisms in vivo and in vitro.MethodsMale C57BL/6J mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity, and mice fed a standard fat diet were used as controls. Then, these mice were treated with SPX or Vehicle by intraperitoneal injection for an additional 12 weeks, respectively. The metabolic profile, fat-browning specific markers and mitochondrial contents were detected. In vitro, 3T3-L1 cells were used to investigate the molecular mechanisms.ResultsAfter 12 weeks of treatment, SPX significantly decreased body weight, serum lipid levels, and improved insulin sensitivity in HFD-induced obese mice. Moreover, SPX was found to promote oxygen consumption in HFD mice, and it increased mitochondrial content as well as the expression of brown-specific markers in white adipose tissue (WAT) of HFD mice. These results were consistent with the increase in mitochondrial content and the expression of brown-specific markers in 3T3-L1 mature adipocytes. Of note, the spexin-mediated beneficial pro-browning actions were abolished by the JAK2/STAT3 pathway antagonists in mature 3T3-L1 cells.ConclusionsThese data indicate that spexin ameliorates obesity-induced metabolic disorders by improving WAT browning via activation of the JAK2/STAT3 signaling pathway. Therefore, SPX may serve as a new therapeutic candidate for treating obesity.

Glucagon-Like Peptide-1: New Regulator in Lipid Metabolism.

Glucagon-like peptide-1 (GLP-1) is a 30-amino acid peptide hormone that is mainly expressed in the intestine and hypothalamus. In recent years, basic and clinical studies have shown that GLP-1 is closely related to lipid metabolism, and it can participate in lipid metabolism by inhibiting fat synthesis, promoting fat differentiation, enhancing cholesterol metabolism, and promoting adipose browning. GLP-1 plays a key role in the occurrence and development of metabolic diseases such as obesity, nonalcoholic fatty liver disease, and atherosclerosis by regulating lipid metabolism. It is expected to become a new target for the treatment of metabolic disorders. The effects of GLP-1 and dual agonists on lipid metabolism also provide a more complete treatment plan for metabolic diseases. This article reviews the recent research progress of GLP-1 in lipid metabolism.

Pomegranate peel polyphenols improves diet-induced obesity and promotes adipose browning development through gut microbiota in mice

Pomegranate peel polyphenols improves diet-induced obesity and promotes adipose browning development through gut microbiota in mice

Grb7 Ablation in Mice Improved Glycemic Control, Enhanced Insulin Signaling, and Increased Abdominal fat Mass in Females.

Growth factor receptor bound protein 7 (GRB7) is a multidomain signaling adaptor. Members of the Grb7/10/14 family, specifically Gbrb10/14, have important roles in metabolism. We ablated the Grb7 gene in mice to examine its metabolic function. Global ablation of Grb7 in FVB/NJ mice was generated. Growth, organ weight, food intake, and glucose homeostasis were measured. Insulin signaling was examined by Western blotting. Fat and lean body mass was measured by nuclear magnetic resonance, and body composition after fasting or high-fat diet was assessed. Energy expenditure was measured by indirect calorimetry. Expression of adiposity and lipid metabolism genes was measured by quantitative PCR. Grb7-null mice were viable, fertile, and without obvious phenotype. Grb7 ablation improved glycemic control and displayed sensitization to insulin signaling in the liver. Grb7-null females but not males had increased gonadal white adipose tissue mass. Following a 12-week high-fat diet, Grb7-null female mice gained fat body mass and developed relative insulin resistance. With fasting, there was less decrease in fat body mass in Grb7-null female mice. Female mice with Grb7 ablation had increased baseline food intake, less energy expenditure, and displayed a decrease in the expression of lipolysis and adipose browning genes in gonadal white adipose tissue by transcript and protein analysis. Our study suggests that Grb7 is a negative regulator of glycemic control. Our results reveal a role for Grb7 in female mice in the regulation of the visceral adipose tissue mass, a powerful predictor of metabolic dysfunction in obesity.

Intestinal dual-specificity phosphatase 6 regulates the cold-induced gut microbiota remodeling to promote white adipose browning

Gut microbiota rearrangement induced by cold temperature is crucial for browning in murine white adipose tissue. This study provides evidence that DUSP6, a host factor, plays a critical role in regulating cold-induced gut microbiota rearrangement. When exposed to cold, the downregulation of intestinal DUSP6 increased the capacity of gut microbiota to produce ursodeoxycholic acid (UDCA). The DUSP6-UDCA axis is essential for driving Lachnospiraceae expansion in the cold microbiota. In mice experiencing cold-room temperature (CR) transitions, prolonged DUSP6 inhibition via the DUSP6 inhibitor (E/Z)-BCI maintained increased cecal UDCA levels and cold-like microbiota networks. By analyzing DUSP6-regulated microbiota dynamics in cold-exposed mice, we identified Marvinbryantia as a genus whose abundance increased in response to cold exposure. When inoculated with human-origin Marvinbryantia formatexigens, germ-free recipient mice exhibited significantly enhanced browning phenotypes in white adipose tissue. Moreover, M. formatexigens secreted the methylated amino acid Nε-methyl-L-lysine, an enriched cecal metabolite in Dusp6 knockout mice that reduces adiposity and ameliorates nonalcoholic steatohepatitis in mice. Our work revealed that host-microbiota coadaptation to cold environments is essential for regulating the browning-promoting gut microbiome.